Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis.

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3ß signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.

Associations between maternal urinary kisspeptin in late pregnancy and decreased fetal growth: a pregnancy-birth cohort study.

Background: Kisspeptin has been indicated to be a biomarker of fetal growth. Although some evidence suggested that maternal kisspeptin concentrations in early pregnancy were associated with increased fetal growth, studies are still limited and the effect of kisspeptin in late pregnancy remains unknown. This study aimed to investigate the associations between maternal kisspeptin in late pregnancy and fetal growth. Methods: Based on the Shanghai-Minhang Birth Cohort study, 724 mother-neonate pairs were included in this study. We measured maternal kisspeptin concentrations in the urine samples collected in late pregnancy and neonatal anthropometric indices at birth. The associations between maternal kisspeptin and neonatal anthropometry were investigated using multiple linear regression models. Results: Higher maternal urinary kisspeptin concentrations were associated with lower neonatal birth weight, head circumference, upper arm circumference, abdominal skinfold thickness, triceps skinfold thickness, and back skinfold thickness. The inverse associations were more pronounced for the highest kisspeptin levels versus the lowest. These patterns were consistent in analyses stratified by neonatal sex, with notably stable associations between maternal kisspeptin concentrations and skinfold thickness. Conclusion: The present study suggested that maternal kisspeptin concentrations in late pregnancy might be inversely associated with fetal growth. The physiological mechanisms of maternal kisspeptin might differ from those in early pregnancy. Further studies are required to assess associations between maternal kisspeptin and energy homeostasis and explore the physiological roles of kisspeptin in late pregnancy.

Ventral tegmental area dopaminergic circuits participates in stress-induced chronic postsurgical pain in male mice.

BACKGROUND: Chronic postsurgical pain (CPP) markedly impairs patients' quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS. METHODS: We conducted CSDS on C57BL/6 J wild-type male mice (n = 12-16 mice/group) and DAT-cre male mice (n = 10-12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC. RESULTS: The ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC. CONCLUSION: CSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

KIRREL promotes the proliferation of gastric cancer cells and angiogenesis through the PI3K/AKT/mTOR pathway.

Anti-angiogenesis is a promising therapeutic strategy for delaying tumour progression that offers, new hope for gastric cancer targeted therapy. The purpose of this study was to investigate the precise mechanism by which Kin of IRRE-like protein 1 (KIRREL) contributes to the development of gastric cancer, particularly in terms of tumour angiogenesis. Differential expression of KIRREL in tissues and cells was detected using quantitative real-time polymerase chain reaction, western blotting and immunohistochemistry. A bioinformatics analysis was conducted to screen for the function and pathway enrichment of KIRREL in gastric cancer. Lentivirus-induced KIRREL silencing in SNU-5 cells and lentivirus-induced KIRREL overexpression in AGS cells were used to study the effect of KIRREL on the proliferation, cell cycle and angiogenesis of gastric cancer cells. Moreover, the expressions of PI3K, P-PI3K, AKT, P-AKT, mTOR, P-mTOR, HIF-1α and VEGF were also detected. Gastric cancer tissues and cells had high levels of KIRREL expression, which is associated with the proliferation, cell cycle and angiogenesis of gastric cancer cells. After silencing and overexpressing KIRREL in SNU-5 and AGS cells, respectively, the proliferation and angiogenesis of SNU-5 cells were inhibited, while the proliferation and angiogenesis of AGS cells were promoted. According to a bioinformatics analysis of the KIRREL gene, angiogenesis regulation and the PI3K/AKT pathway were highly connected. The PI3K/AKT/mTOR pathway was repressed and stimulated by KIRREL silencing and overexpression, respectively. IGF-1, an AKT agonist, and LY294002, an inhibitor, reversed the effects of KIRREL silencing and overexpression on the PI3K/AKT/mTOR pathway and on gastric cancer cell proliferation and angiogenesis. KIRREL may mediate the proliferation and angiogenesis of gastric cancer cells through the PI3K/AKT/mTOR signalling pathway. These findings could help in the further development of potential anti-angiogenesis targets.

Single-cell analyses implicate ascites in remodeling the ecosystems of primary and metastatic tumors in ovarian cancer.

Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8+ T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived ontogeny, whereas macrophages in ascites were more of embryonic origin. Furthermore, we characterized MAIT and dendritic cells in malignant ascites, as well as two endothelial subsets in primary tumors as predictive biomarkers for platinum-based chemotherapy response. Taken together, our study provides a global view of the female malignant ascites ecosystem and offers valuable insights for its connection with tumor tissues and paves the way for potential markers of efficacy evaluation and therapy resistance in OC.

A potential primary method for peptide purity analysis by gas chromatography-isotope dilution infrared spectrometry.

Here we proposed a method for peptide purity analysis using gas chromatography-isotope dilution infrared spectroscopy. The principle and feasibility of the proposed measurement method were investigated. The derivatization, separation, and infrared detection conditions for amino acids were optimized, and the performance of the method was investigated. Then, the proposed method was used for assessment of [Glu1]-fibrinopeptide B purity, and the results were compared with those obtained by high performance liquid chromatography-isotope dilution mass spectrometry. The average purity of six sub-samples using the proposed method was (0.755 ± 0.017) g/g, which agreed well with that obtained by isotope dilution mass spectrometry (0.754 ± 0.012) g/g. The repeatability of the proposed method was 2.2%, which was similar to that of isotope dilution mass spectrometry (1.7%). The proposed method has a similar principle and had similar accuracy, precision, and linearity to isotope dilution mass spectrometry; however, the developed method had higher limit of detection (LOD) and limit of quantitation (LOQ) values because of the low sensitivity of infrared detection. The results were also Système International d'Unités (SI) traceable. The developed method has the advantage of lower cost compared with isotope dilution mass spectrometry because only one isotope-labeled atom in an analog is required, and several infrared spectra can be extracted, averaged, and used for an amino acid calculation during one run, potentially leading to higher accuracy. This method could be easily expanded to the accurate quantitation of other organic compounds, including proteins. It is expected that the proposed method will be widely used in chemical and biological measurements as a new primary method.

Paris saponins â ¦ inhibits glycolysis of ovarian cancer via the RORC/ACK1 signaling pathway.

Rhizoma Paridis is a traditional Chinese medicine commonly used for treatment of malignant tumors. Paris saponins Ⅶ (PSⅦ) is one of the components of Rhizoma Paridis, but the role of PSⅦ in glucose metabolism in ovarian cancer remains elucidated. A series of experiments in the current study demonstrated that PSⅦ inhibites glycolysis and promotes cell apoptosis in ovarian cancer cells. Expression levels of glycolysis-related proteins and apoptosis-related proteins were significantly altered by upon treatment with PSⅦ, as determined from western blot analyses. Mechanistically, PSⅦ exerted its anti-tumor effects by targeting the RORC/ACK1 signaling pathway. These findings indicate that PSⅦ inhibits glycolysis-induced cell proliferation and apoptosis through the RORC/ACK1 pathway, supporting its potential development as a candidate chemotherapeutic agent for ovarian cancer.

The function and mechanisms of action of circular RNAs in Urologic Cancer.

Kidney, bladder, and prostate cancer are the three major tumor types of the urologic system that seriously threaten human health. Circular RNAs (CircRNAs), special non-coding RNAs with a stabile structure and a unique back-splicing loop-forming ability, have received recent scientific attention. CircRNAs are widely distributed within the body, with important biologic functions such as sponges for microRNAs, as RNA binding proteins, and as templates for regulation of transcription and protein translation. The abnormal expression of circRNAs in vivo is significantly associated with the development of urologic tumors. CircRNAs have now emerged as potential biomarkers for the diagnosis and prognosis of urologic tumors, as well as targets for the development of new therapies. Although we have gained a better understanding of circRNA, there are still many questions to be answered. In this review, we summarize the properties of circRNAs and detail their function, focusing on the effects of circRNA on proliferation, metastasis, apoptosis, metabolism, and drug resistance in kidney, bladder, and prostate cancers.

Effects of endovascular recanalization on symptomatic non-acute occlusion of intracranial arteries.

To investigate the effect and safety of recanalization surgery for non-acute occlusion of large intracranial arteries and factors affecting clincial outcomes. Patients with non-acute occlusion of internal carotid artery (ICA), middle cerebral artery (MCA), and vertebrobasilar artery (VBA) treated with recanalization were retrospectively enrolled. The clinical and angiographic data were analyzed. 177 patients were enrolled, including 67 patients with intracranial ICA occlusion, 52 with MCA occlusion, and 58 with VBA occlusion. Successful recanalization was achieved in 152 (85.9%) patients. Complications occurred in 15 patients (8.5%). Followed up for 3-7 months, the 90 day mRS was significantly improved compared with that before the procedure. Among 152 patients with successful recanalization, eight patients experienced reocclusion (5.3%), and 11 patients experienced restenosis (7.2%). Successful recanalization was significantly (P < 0.05) associated with occlusion duration, calcification or angulation of the occluded segment. Complications were significantly (P < 0.05) associated with location of occlusion, hyperlipidemia, and patients' height. Restentosis or reocclusion at follow-up was significantly (P < 0.05) associated with complications and mRS at 90 days. The significant (P < 0.05) independent risk factors were angulation and calcification for successful recanalization, hyperlipidemia for complications, and mRS at 90 days for restenosis or reocclusion at follow-up. Recanalization surgery may be a safe and effective approach for patients with non-acute symptomatic occlusion of large intracranial arteries, and factors significantly independently associated with successful recanalization, periprocedural complications and restenosis or reocclusion after surgery have been identified for future reference to improve clinical outcomes.

Comparison of drug-coated balloon with conventional balloon for angioplasty in symptomatic intracranial atherosclerotic stenosis.

BACKGROUND: Drug-coated balloon (DCB) angioplasty has been studied for reducing the occurrence of restenosis after treatment for intracranial atherosclerotic stenosis (ICAS), but no comparison has been published of the use of drug-coated and non-coated balloons in angioplasty for ICAS. We aim to compare the safety and efficacy of DCB angioplasty with conventional balloon (CB) angioplasty for the treatment of symptomatic ICAS. METHODS: One hundred cases with symptomatic ICAS treated with DCB (n=49) and CB (n=51) angioplasty were retrospectively analyzed. 1:1 propensity score matching (PSM) was completed to eliminate bias in the patients selected for further analysis. The periprocedural events and follow-up outcomes between the two groups were compared. RESULTS: There were 32 cases in each group after PSM. Technical success (<50% residual stenosis) was achieved in 30 cases (93.8%) in the DCB group and in 28 cases (87.5%) in the CB group. The rates of stroke or mortality within 30 days were 3.1% in the DCB group and 6.3% in the CB group (p=1). The incidence of restenosis in the DCB group (6.3%) was significantly lower than that in the CB group (31.3%) (p=0.01). CONCLUSIONS: Compared with CB angioplasty, DCB angioplasty can effectively reduce the incidence of restenosis. Further studies are needed to validate the role of DCB angioplasty in the management of symptomatic ICAS.

Ultrasound-Amplified Enzyodynamic Tumor Therapy by Perovskite Nanoenzyme-Enabled Cell Pyroptosis and Cascade Catalysis.

Overcoming apoptosis resistance to achieve efficient breast cancer treatment remains a challenge. The precise induction of another form of programmed cell death, pyroptosis, is an excellent alternative for treating cancer. Ultrasound (US)-enhanced enzyme dynamic (enzyodynamic) therapy is developed by employing LaFeO3 (LFO) perovskite nanocrystals as a substrate to increase the rate of deleterious reactive oxygen species (ROS) generation for intensive cell pyroptosis. LFO nanocrystals possess quadruple enzyme-mimicking activities, including oxidase-, peroxidase-, glutathione peroxidase-, and catalase-mimicking activities, which undertake the dominant therapeutic task through cascade catalytic reactions, including the reversal of hypoxic microenvironment, depletion of endogenous glutathione, and continuous output of ROS. US exogenous stimulation increases the transition rate of the intermediate complex to Fe (II) and favors incremental ROS production, by which the ROS burst-induced pyroptosis process is accomplished through the ROS-TXNIP-NLRP3-GSDMD pathway. Both in vitro and in vivo antineoplastic outcomes affirm the ascendancy of LFO nanozyme-induced pyroptosis. This work highlights the critical role of US coupled with nanocatalytic reactors in pyroptosis-dominant breast cancer treatment with the apoptosis resistance circumvention feature.

circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer.

BACKGROUND: Circular RNAs (circRNAs) generated by back-splicing of precursor mRNAs (pre-mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. METHODS: circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull-down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). RESULTS: Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial-mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. CONCLUSIONS: These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.

Gestational exposure to bisphenol analogues and kisspeptin levels in pregnant women and their children: A pregnancy-birth cohort study.

Gestational exposure to bisphenol analogues (BPs)，especially bisphenol A (BPA), has been associated with adverse pregnancy-related outcomes and altered reproductive development of offspring, but the underlying mechanisms are not well documented. Kisspeptin, a key regulator of reproductive health, could be the potential target for endocrine disrupting compounds like BPs. Among 528 mother-child pairs, we investigated the associations of gestational BPs exposure with kisspeptin levels in two critical life stages, pregnancy and pre-puberty. Maternal BPs and kisspeptin concentrations were measured in urine samples collected in the third trimester. Children's urine samples were collected at 6-year visit and analyzed for kisspeptin levels. Associations were observed between BPA and its alternatives and lower kisspeptin in pregnant women but higher kisspeptin in their children. In contrast, TCBPA was suggestively associated with higher kisspeptin in pregnant women but lower kisspeptin in children. Our study provides the first epidemiologic evidence that gestational exposure to selected BPs may be associated with altered kisspeptin system in both pregnant women and their children, sheds some light on the potential mechanisms underlying the various reproductive health outcomes following gestational BPA exposure, and suggests potential reproductive toxicities of other BPs in humans.

Angiographic Characteristics of Cerebral Perfusion and Hemodynamics of the Bridging Artery After Surgical Treatment of Unilateral Moyamoya Disease.

Purpose: To investigate the characteristics of cerebral perfusion and hemodynamics of bypass grafting in the treatment of moyamoya disease (MMD) using the iFlow color-coded flow map in comparison with magnetic resonance imaging-perfusion-weighted imaging (MRI-PWI) and computational fluid dynamic (CFD) analysis. Materials and Methods: Patients with MMD treated with bypass grafting who had undergone MRI PWI and digital subtraction angiography for iFlow color-coded map was retrospectively enrolled and CFD was performed for calculating the hemodynamic stresses around the bypass grafting. Results: Forty-five patients with unilateral MMD treated with bypass surgery were enrolled. The bypass surgery was successful in all patients, with no severe neurological complications during the periprocedural period. Followed up for 4-12 months (median 5.5), the neurological function was good in all patients. The cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) were significantly (p < 0.05) improved in the middle cerebral artery distribution area on the surgical side before and after vascular bypass, and the difference of TTP (s) measured from the proximal bifurcation of common carotid artery to the confluence of sinus was also significant (p < 0.05). A significant (p < 0.05) positive correlation existed in the perfusion parameters between the iFlow blood perfusion and the MRI-PWI perfusion, with r-value for TTP of 0.765 (p < 0.01). The iFlow color-coded blood flow map showed warm color changes on the diseased side, similar to those on the contralateral side. In CFD analysis, the hemodynamic stresses were all improved, in and around the bypass grafting and distal vessels, which were beneficial to blood flow entering distal arterial branches. Conclusion: The iFlow color-coded flow map can be used to analyze cerebral perfusion after bypass grafting for MMD, similar to MRI-PWI, and CFD can be used to analyze the hemodynamics after bypass grafting, revealing improved hemodynamics to promote blood flow entering distal arteries.

Stanniocalcin 1 promotes metastasis, lipid metabolism and cisplatin chemoresistance via the FOXC2/ITGB6 signaling axis in ovarian cancer.

BACKGROUND: Stanniocalcin 1 (STC1) plays an integral role in ovarian cancer (OC). However, the functional role of STC1 in metastasis, lipid metabolism and cisplatin (DDP) chemoresistance in OC is not fully understood. METHODS: Single-cell sequencing and IHC analysis were performed to reveal STC1 expression profiles in patient tissues. Metastasis, lipid metabolism and DDP chemoresistance were subsequently assessed. Cell-based in vitro and in vivo assays were subsequently conducted to gain insight into the underlying mechanism of STC1 in OC. RESULTS: Single-cell sequencing assays and IHC analysis verified that STC1 expression was significantly enhanced in OC tissues compared with para-carcinoma tissues, and it was further up-regulated in peritoneal metastasis tissues compared with OC tissues. In vitro and in vivo experiments demonstrated that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance in OC. Simultaneously, STC1 promoted lipid metabolism by up-regulating lipid-related genes such as UCP1, TOM20 and perilipin1. Mechanistically, STC1 directly bound to integrin ß6 (ITGB6) to activate the PI3K signaling pathway. Moreover, STC1 was directly regulated by Forkhead box C2 (FOXC2) in OC. Notably, targeting STC1 and the FOXC2/ITGB6 signaling axis was related to DDP chemoresistance in vitro. CONCLUSIONS: Overall, these findings revealed that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance via the FOXC2/ITGB6 signaling axis in OC. Thus, STC1 may be used as a prognostic indicator in patients with metastatic OC. Meanwhile, STC1 could be a therapeutic target in OC patients, especially those who have developed chemoresistance to DDP.

The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells.

BACKGROUND: Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets. METHODS: RNA sequencing of cisplatin-resistant and -sensitive (chemoresistant and chemosensitive, respectively) ovarian cancer organoids was performed, followed by detection of the expression level of fibrillin-1 (FBN1) in organoids and clinical specimens of ovarian cancer. Subsequently, glucose metabolism, angiogenesis, and chemosensitivity were analyzed in structural glycoprotein FBN1-knockout cisplatin-resistant ovarian cancer organoids and cell lines. To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, and FÓ§rster resonance energy transfer-fluorescence lifetime imaging analyses were performed, followed by in vivo assays using vertebrate model systems of nude mice and zebrafish. RESULTS: FBN1 expression was significantly enhanced in cisplatin-resistant ovarian cancer organoids and tissues, indicating that FBN1 might be a key factor in chemoresistance of ovarian cancer. We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo, which promoted the cisplatin-resistance of ovarian cancer. Knockout of FBN1 combined with treatment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells. Mechanistically, FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) at the Tyr1054 residue, which activated its downstream focal adhesion kinase (FAK)/protein kinase B (PKB or AKT) pathway, induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2) at the tyrosine residue 690 (Tyr690), promoted the nuclear translocation of STAT2, and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis. CONCLUSIONS: The FBN1/VEGFR2/STAT2 signaling axis may induce chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

Multi-kingdom microbiota analyses identify bacterial-fungal interactions and biomarkers of colorectal cancer across cohorts.

Despite recent progress in our understanding of the association between the gut microbiome and colorectal cancer (CRC), multi-kingdom gut microbiome dysbiosis in CRC across cohorts is unexplored. We investigated four-kingdom microbiota alterations using CRC metagenomic datasets of 1,368 samples from 8 distinct geographical cohorts. Integrated analysis identified 20 archaeal, 27 bacterial, 20 fungal and 21 viral species for each single-kingdom diagnostic model. However, our data revealed superior diagnostic accuracy for models constructed with multi-kingdom markers, in particular the addition of fungal species. Specifically, 16 multi-kingdom markers including 11 bacterial, 4 fungal and 1 archaeal feature, achieved good performance in diagnosing patients with CRC (area under the receiver operating characteristic curve (AUROC) = 0.83) and maintained accuracy across 3 independent cohorts. Coabundance analysis of the ecological network revealed associations between bacterial and fungal species, such as Talaromyces islandicus and Clostridium saccharobutylicum. Using metagenome shotgun sequencing data, the predictive power of the microbial functional potential was explored and elevated D-amino acid metabolism and butanoate metabolism were observed in CRC. Interestingly, the diagnostic model based on functional EggNOG genes achieved high accuracy (AUROC = 0.86). Collectively, our findings uncovered CRC-associated microbiota common across cohorts and demonstrate the applicability of multi-kingdom and functional markers as CRC diagnostic tools and, potentially, as therapeutic targets for the treatment of CRC.

Long non-coding RNA CTSLP8 mediates ovarian cancer progression and chemotherapy resistance by modulating cellular glycolysis and regulating c-Myc expression through PKM2.

PURPOSE: Long non-coding RNAs (lncRNAs) play vital roles in tumor progression and resistance. Ovarian cancer (OC), a common gynecological cancer, is associated with poor prognosis as it can progress to peritoneal metastasis and develop resistance to chemotherapy. This study aimed to examine the role of lncRNAs in the development of chemotherapy resistance in OC. METHODS: The clinical samples were divided into chemotherapy-sensitive and chemotherapy-resistant groups based on the chemotherapy response at follow-up. The glycolysis levels in the two groups were analyzed using positron emission tomography/computed tomography (PET/CT) scanning and immunohistochemistry. GEO dataset analysis revealed the expression of CTSLP8 in chemotherapy-resistant patients with OC. Two pairs of normal and diamminodichloroplatinum (DDP)-resistant cells were transfected with CTSLP8 overexpression and knockdown constructs to examine the functions of CTSLP8 in the OC cells and elucidate the underlying mechanisms. The in vivo effect of CTSLP8 overexpression and knockdown on the chemotherapy response of tumors was examined using a mouse subcutaneous tumor model. The tissue chips were subjected to fluorescence in situ hybridization and immunohistochemical (IHC) staining to examine the correlation among CTSLP8 expression, DDP resistance, and prognosis in OC. RESULTS: The dataset analysis demonstrated that CTSLP8 was upregulated in chemotherapy-resistant tumor tissues. CTSLP8 promoted the proliferation and development of DDP resistance in the OC cells. Moreover, CTSLP8 promoted c-Myc expression by facilitating the binding of PKM2 to the promoter region of c-Myc, thereby upregulating glycolysis. The analysis of tissue chips revealed that the upregulation of CTSLP8 was associated with the development of DDP resistance and poor prognosis in patients with OC. CONCLUSIONS: These findings indicate that CTSLP8 forms a complex with PKM2 to regulate c-Myc, and this action results in the upregulation of cellular glycolysis, consequently promoting OC progression and development of chemotherapy resistance. HEADLIGHTS: 1. CTSLP8 was upregulated in the chemotherapy-resistant tumor tissues. 2. CTSLP8 promoted the proliferation and cisplatin resistance in the OC cells. 3. CTSLP8 promoted glycolysis by facilitating the binding of PKM2 to the promoter region of c-Myc. 4. Inhibition of CTSLP8 or the combination of c-Myc inhibitors with cisplatin were potential therapeutic strategies for chemotherapy-resistant of OC.

Stanniocalcin-2 promotes cell EMT and glycolysis via activating ITGB2/FAK/SOX6 signaling pathway in nasopharyngeal carcinoma.

Stanniocalcin-2 (STC2) has been proved to regulate a variety of signaling pathways including cell growth, metastasis, and therapeutic resistance. However, the role of STC2 in the regulation of nasopharyngeal carcinoma (NPC) remains poorly understood. In this study, we investigated the regulatory function of STC2 on epithelial-mesenchymal transition (EMT) and glycolysis traits in NPC and revealed the underlying molecular mechanisms. We found that STC2 was highly expressed in primary nasopharyngeal carcinoma tissues and lymph node metastatic tissues. Silencing of STC2 inhibited cell proliferation, invasion, and glycolysis. Further analyses for the clinical samples demonstrated that STC2 expression was associated with the poor clinical progression. Moreover, we demonstrated the interaction of ITGB2 with STC2 and its involvement in STC2-mediated ITGB2/FAK/SOX6 axis. Collectively, our results provide new insights into understanding the regulatory mechanism of STC2 and suggest that the STC2/ITGB2/FAK/SOX6 signaling axis may be a potential therapeutic target for NPC.